Thyroid hormone plays a crucial role in the development of the nervous system by inducing a variety of anatomical, physiological, biochemical, and molecular events during critical periods. One in every 40000 newborns have congenital hypothyroidism that will lead to growth deficiencies and irreversible mental retardation unless thyroid hormone treatment begins within the first four weeks of life. In addition hypothyroidism results in several neurological disorders in adults, including reduction or loss of olfactory abilities. The thrust of this proposal is to determine the influence of thyroid hormone on the development of the olfactory system using a model system-the olfactory epithelium of the clawed frog, Xenopus laevis. Adult Xenopus have a tripartite olfactory system that consists of olfactory epithelium in the principal and middle cavities and vomeronasal epithelium in the vomeronasal organ. Different classes of odorant receptor genes have been isolated from the adult principal cavity and middle cavity that resemble mammalian and fish odorant receptor genes respectively. The adult olfactory structures are formed at metamorphosis when the middle cavity develops de novo and the principal cavity undergoes radical cellular and biochemical transformations. The specific aims of the current proposal are to: (1) determine whether thyroid hormone is required for development of the middle cavity, (2)determine whether all the receptor cells in the principal cavity die and are replaced at metamorphosis, (3) determine the temporal and spatial expression patterns of mammalian-like and fish-like odorant receptor genes, and (4) determine whether thyroid hormone levels influence the cellular changes and odorant receptor gene expression patterns in the developing olfactory epithelium. These goals will be accomplished with hormonal manipulations, immunocytochemistry, electron microscopy, neuronal tract tracing, RT-PCR, and in situ hybridization. The goal of this research is to provide insight into thyroid hormone regulation of olfactory system development using an experimentally-favorable model system.